Pyrrolidine and piperidine compounds

Patent metadata

Field	Value
Publication number	US-11655235-B2
Application number	US-202017090552-A
Country	US
Kind code	B2
Filing date	Nov 5, 2020
Priority date	Nov 6, 2019
Publication date	May 23, 2023
Grant date	May 23, 2023

Abstract

The present technology provides pyrrolidine and piperidine compounds or pharmaceutically acceptable salts thereof, preparation processes thereof, pharmaceutical compositions comprising the same, and uses thereof. In particular, said compounds may be usefully applied in the treatment and prevention of FAP-mediated diseases.

First claim

What is claimed is:

1. A compound of Formula 1:

or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof,
wherein:
n is 1 or 2;
R 1 is selected from the group consisting of Formulas I, II, III, IV, and V:

R 2 is a hydrogen or a C 1-3 alkyl;
R 3 is: a 5- to 12-membered heteroaryl, wherein said heteroaryl contains 1 to 3 heteroatoms independently selected from O, N, and S and is optionally substituted by 1 to 3 Z,
a 3- to 12-membered non-aromatic heterocycle, wherein said heterocycle contains 1 to 3 heteroatoms independently selected from O, N, and S and is optionally substituted by 1 to 3 Z,
—NR 4 R 5 , —OR 4 , —C(O)NHR 4 , —NHC(O)(CH 2 ) m R 4 , —NHS(O) 2 R 4 , —(CH 2 ) m CH 2 R 4 , or —(CH 2 ) m NHR 4 ,
wherein m is 0 or 1;

R 4 is: a phenyl substituted with 1 to 3 Z,
a heterocycle selected from the group consisting of benzo[d][1,3]dioxolyl, dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, 2-oxo-1,2-dihydroquinolinyl, and 2-oxo-1,2,3,4-tetrahydroquinolinyl, wherein said heterocycle is optionally substituted with 1 to 3 Z,
a naphthyl optionally substituted with 1 to 3 Z, or
a heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl, and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1 to 3 Z;

R 5 is a hydrogen or a C 1-3 alkyl;
each Z is independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, carboxylic acid, C 1-5 alkyl optionally substituted by 1 to 3 Z 1 , C 2-6 alkenyl optionally substituted by Z 1 , C 2-6 alkynyl optionally substituted by Z 1 , C 1-5 alkoxy optionally substituted by 1 to 3 Z 1 , C 1-5 alkylthio optionally substituted by Z 1 , mono- or di-C 1-5 alkylamino optionally substituted by Z 1 , piperazinyl optionally substituted by Z 1 , C 1-5 alkylsulfonylamino optionally substituted by Z 1 , C 1-5 alkylcarbonylamino optionally substituted by Z 1 , aminosulfonyl optionally substituted by Z 1 , aminocarbonyl optionally substituted by Z 1 , C 1-5 alkylaminocarbonyl optionally substituted by Z 1 , phenyl optionally substituted by Z 1 , phenoxy optionally substituted by Z 1 , benzyl optionally substituted by Z 1 , benzoyl optionally substituted by Z 1 , phenylaminocarbonyl optionally substituted by Z 1 , pyrazolyl optionally substituted by Z 1 , benzoxazolyl optionally substituted by Z 1 , C 1-5 alkoxycarbonyl optionally substituted by Z 1 , benzyloxy optionally substituted by Z 1 , C 1-5 alkylsulfonyl optionally substituted by Z 1 , acetyl, morpholinyl optionally substituted by Z 1 , —NR 6 C(O)R 7 , and —C(O)NR 6 R 7 ;
wherein each Z 1 is independently selected from halogen, hydroxyl, amino, C 1-5 alkylamino, cyano, acetyl, C 1-5 alkyl, C 1-5 haloalkyl, C 3-6 carbocycle, and C 3-6 heterocycle, wherein said C 3-6 carbocycle and said C 3-6 heterocycle are optionally substituted with halogen, hydroxyl, C 1-5 alkyl, or C 1-5 haloalkyl;
R 6 is hydrogen or a C 1-3 alkyl group;
R 7 is: a C 1-3 alkyl group optionally substituted with phenyl,
a phenyl optionally substituted with 1 to 3 Z 2 , or
a heteroaryl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, pyrrolyl, thiophenyl, quinolinyl, isoquinolinyl, chromenonyl, quinazolinyl, benzoxazolyl, benzofuranyl, benzothiophenyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, furo[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, isoxazolyl, acridinyl, and naphthyridinyl, wherein said heteroaryl is optionally substituted with 1 to 3 Z 2 ; and

each Z 2 is independently selected from the group consisting of hydroxy, amino, halogen, cyano, nitro, hydroxycarbonyl, C 1-5 alkyl optionally substituted by 1 to 3 Z 3 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-5 alkoxy optionally substituted by 1 to 3 Z 3 , C 1-5 alkylthio, mono- or di-C 1-5 alkylamino, piperazinyl optionally substituted by Z 3 , C 1-5 alkylsulfonylamino, C 1-5 alkylcarbonylamino, aminosulfonyl, aminocarbonyl, C 1-5 alkylaminocarbonyl, phenyl, phenoxy, benzyl, benzoyl, phenylaminocarbonyl, pyrazolyl, and benzoxazolyl;
wherein each Z 3 is independently selected from halogen, amino, and acetyl.

2. The compound according to claim 1 , or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of Formulas Ia, IIa, IIIa, IVa, and Va:

3. The compound according to claim 1 , or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, having a structure of Formula 1a:

4. The compound according to claim 3 , or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.

5. The compound according to claim 3 , or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R 5 is a C 1-3 alkyl.

6. The compound according to claim 1 , or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, having a structure of Formula 1b:

7. The compound according to claim 1 , or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, having a structure of Formula 1c:

8. The compound according to claim 1 , or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, having a structure of Formula 1d:

9. The compound according to claim 8 , or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein m is 0.

10. The compound according to claim 8 , or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein m is 1.

11. The compound according to claim 1 , or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, having a structure of Formula 1e:

12. The compound according to claim 1 , or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of —NR 4 R 5 , —OR 4 , —C(O)NHR 4 , —NHC(O)(CH 2 ) m R 4 , and —NHS(O) 2 R 4 .

13. The compound according to claim 1 , or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R 4 is a phenyl substituted with 1 to 3 Z, wherein each Z is

Assignees

• Yuhan Corp

Inventors

• Dong Tae Han
• Park Yoo Hoi
• Kim Tae Kyun
• Joo Jae Eun
• Jung Eun Hye
• Jeong Jae Won
• Lee Hyun Seung
• Kim Do Hoon
• Yang Ji Eun
• Park Jun Chui
• Lim Sang Myoun
• Ha Na Ry
• Chung Da In
• Gal Ji Yeong

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/423

  condensed with carbocyclic rings · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• A61K31/4025

  not condensed and containing further heterocyclic rings, e.g. cromakalim · CPC title